title: Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion.
abstract: Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca(2+) mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca(2+) and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca(2+) concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.forename: Robert
authors.initials: R
authors.lastname: Wondergem
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Shen
authors.forename: Greg
authors.initials: G
authors.lastname: Cavey
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Ke
authors.forename: Ryan
authors.initials: R
authors.lastname: Thompson
authors.forename: Robert
authors.initials: R
authors.lastname: Bradley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daugherty-Holtrop
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daughtery-Holtrop
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.forename: Hanan
authors.initials: H
authors.lastname: Omar
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: David
authors.initials: D
authors.lastname: Wenkert
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
mesh_terms: D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism / Q000494:pharmacology; D008823:Micelles; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008823:Micelles; D050994:Voltage-Dependent Anion Channels; C112765:tanespimycin